Towards multi-component pharmaceutical solid forms through crystal engineering

Combining APIs with specific molecules in a single crystal form shows potential during the development of new drug solid forms. Compared to the physical mixture, combination through crystallization can not only lead to improved manufacture processes and also allows improving the physical properties of APIs. Traditional crystal engineering methods like cocrystallization and salt formation have been widely studied in the context of multi-component systems. In this work, we explored some novel crystal engineering methodologies leading to multi-component systems. Our first attempt relies upon the use of an organic linker to combine two drugs. We focused on the use of urea as a bridge, but this technique did not lead to the desired results. Based on this result, we decided to turn to a different type of interaction, using complexation as a tool. Doing so, we were able to show sweeteners and racetams, pyridine containing drugs and carboxylic acid containing drugs, were successfully combined. Finally, we investigate an interesting system consisting of a solid solution involving the drugs piracetam and S-oxiracetam and a third coformer gallic acid. Solid solutions allow fine-tuning of the amount of piracetam vs S-oxiracetam. In conclusion, this thesis not only presented dozens of new multi-component pharmaceutical crystals with improved physical properties but also demonstrated two innovative methodologies for designing and synthesizing multi-component crystals including complexation and cocrystal solid solution. With the guidance of structure analysis, uncombined molecules (in traditional method) could be bond in one crystal with a desired ratio. There are still plenty of unexplored areas in pharmaceutical crystal design beyond traditional pharmaceutical solid state like salt formation or cocrystallization.